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Genetic counseling: Becker Muscular Dystrophy
Becker Muscular Dystrophy General Information *Dystrophinopathies **Characterized by a spectrum of muscle disease that ranges from mild to severe **Duchenne/Becker muscular dystrophy is severe ***Skeletal muscle is primarily affected in both ***DMD is rapidly progressive and presents in early childhood. ****Patients are often wheelchair-bound by age 12 ***Becker is characterized by later-onset skeletal muscle weakness ****Patients remain ambulatory into their 20s ****Despite milder skeletal muscle involvement, heart failure from dilated cardiomyopathy is a common cause of morbidity and the most common cause of death ****Mean age of death is in the mid-40s *Dystrophin gene **Xp21.2 **Encodes protein dystrophin **85% of males with BMC have deletions or duplications involving exons of this gene **Molecular genetic testing is available clinically *Prevalence **1 in 18,000 live male births Diagnosis *Clinical **Family history ***Compatible with X-linked recessive inheritance **Creatine Phosphokinase (CK) concentration ***Evaluated by blood test ***Elevated serum CK concentration results from progressive elimination of dystrophic muscle fibers. ****Can also result from strenuous exercise ***CK concentration gradually decreases with advancing age due to the progressive elimination of these muscle fibers. ***100% of males with BMD have a serum CK concentration >5x normal ***~30% of female carriers have a concentration 2-10x normal ****Some investigations have shown a wide variability in BMD carriers ****Many have levels within the normal range, so other tests are necessary ****CPK is not completely reliable **Clinical findings ***Progressive symmetrical muscle weakness and atrophy, proximal greater then distal, often with calf hypertrophy ****Weakness of quadriceps femoris may be the only sign ***Activity-induced cramping in some patients ***Flexion contractus of the elbows may occur late in the course ***Wheelchari dependency, if present, after 16 years of age ***Preservation of neck flexor muscle strength in BMD differentiates it from DMD *Molecular genetic testing **Deletions involving one or more exons of the DMD gene ***~85% of males with BMD have deletions ***Testing is done by PCR or southern blot ***Available on a clinical basis **The remaining ~15% have duplications of one or more exons of the DMD gene or other mutations such as small deletions or insertions, single base changes, or splicing mutations **Carrier testing may be performed but requires quantitative analysis for gene dosage which can be difficult to perform and interpret **Prenatal testing is available Clinical Description *Males **Characterized by later-onset skeletal muscle weakness (as compared to DMD which presents ~ age 4 years) ***Patients remain ambulatory into their 20s with BMD **Heart failure from dilated cardiomyopathy is a common cause of morbidity and the most common cause of death **The mild end of the spectrujm includes men with onset of symptoms after age 30 years who remain ambulatory even into their 60s **Cognitive impairment is not as common or as sever as in DMD *Females **Occasionally have clinical features as the result of X chromosome rearrangements involving the DMD locus (Xp21.2) **81% of BMD carriers have no signs or symptoms **14% have mild to moderate muscle weakness **16% have left ventricle dilation **5% have myalgia or cramps **No BMD carrier females have been found to have dilated cardiomyopathy *Genotype-Phenotype Correlations **In males, phenotypes are best correlated with the degree of expression of dystrophin, which is largely determine by the reading frame of the spliced messaged obtained from the deleted allele **The BMD phenotype occurs when there is some dystrophin, usually resulting from: ***Deletions or duplications that juxtapose "in-frame" exons ***Some splicing mutations ***Most non-truncating single base changes that result in translation of a protein product with intact N or C termini **A dystrophin protein that retains partial function produces the milder BMD phenotype *Management **There is no treatment for BMD **Appropriate management can prolong survival and improve quality of life ***Physical therapy to promote mobility ****Range-of-motion exercises ***Braces to delay the onset of contractures ***Monitoring and surgical intervention for orthopedic complications ****Scoliosis, kyphosis, or lordosis ***Routine monitoring for evidence of cardiomyopathy **All carriers should have a complete cardiac evaluation at least once Differential Diagnosis *Limb-girdle muscular dystrophy **A group of disorders clinically similar to DMD **Occurs in both sexes **Caused by mutations I genes that encode sarcoglycans and other proteins that interact with dystrophin *Emery-Dreifuss muscular dystrophy **Associated with limb contractures and cardiac arrhythmia *X-linked recessive, autosomal dominant, and autosomal recessive forms **Caused by mutations in the LMNA gene *Spinal muscular atrophy **Caused by mutations in the SMN gene **Characterized by: ***Poor muscle tone ***Symmetric muscle weakness that spares the face and ocular muscles ***Evidence of anterior horn cell involvement ****Includes fasciculations of the tongue and absence of deep tendon reflexes *Dilated cardiomyopathy **Can be sporadic or familial *No other phenotypes are associated with mutations in the DMD gene Inheritance *X-linked recessive **Carrier females have a 50% chance of transmitting the BMD mutation in each pregnancy **With each pregnancy, a carrier has a 25% chance of having an affected child *Risk to family members **A woman with an affected son and one other affected relative in the maternal line is an obligate heterozygote **A woman with more than one affected son and no other family history can have: ***A germline mutation ****DMD disease-causing mutation present in every cell ***Germline mosaicism ****Mosaicism for a DMD disease-causing mutation which includes the germline ****The frequency of germline mosaicism in DMD is estimated at 12% to 20% **If proband is only affected family member, must determine if mother and other females are carriers ***The proband may have a de novo DMD disease-causing mutation ****The mutation could have occurred in the egg at the time of conception ****The mutation could have occurred after conception and therefore is present in some but not all cells of the proband's body. ****The likelihood that the mother is a carrier is low ***The proband's mother may have a de novo mutation ****2/3 of mothers of sporadically occurring males with DMD are carriers ****Could have occurred if: *****Mutation occurred in the egg or sperm at the time of her conception and is present in every cell of her body (germline mutation) *****Mutation is present in some but not all cells of her body (somatic mosaicism) *****Mutation is present only in her egg cells (germline mosaicism) and is not detected in a blood sample. ***The proband's mother may have inherited a DMD mutation from her mother who is a carrier, her mother or father who has somatic mosaicism, or her mother or father who has germline mosaicism. Risk Assessment *All daughters of a male affected with BMD are carriers; none of the sons will inherit the mutation Ordering the test *Patient must sign consent form for DNA analysis **Use blue ink so it is obvious which is the original **Give the patient a copy **Put the original in the chart *Use special specimen processing request form **Make a copy for the chart **Give a copy to Lori Martineek at E352 *Blood is drawn at Test Referral Center **Pt must have consent form, 2-ply specimen processing request form, and DNA analysis requisition **Tell pt to make sure her name is on the tube of blood **TRC will FedEx to Dr. Prior's lab *Contact Dr. Thomas W. Prior to inform him that you are sending the sample **Prior-1@medctr.osu.edu **Give him clinical history and lab report # from prior testing Resources *Muscular Dystrophy Association **800-572-1717 **http://www.mdausa.org References *Emery and Rimoin's Principles and Practice of Medical Genetics. Third Edition, 1996. pp 2337-2354 *National Organization for Rare Disorders (NORD) *Nelson's Textbook of Pediatrics. 15th Edition. pp1745-1748 *Online Mendelian Inheritance in Man (OMIM). BMD#300376 *www.geneclinics.org (GeneReviews) Notes The information in this outline was last updated in 2002. Material obtained under GFDL Licence from http://en.wikibooks.org/wiki/Handbook_of_Genetic_Counseling